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RESEARCH ARTICLE Am. J. PharmTech Res. 2018; 8(5) ISSN: 2249-3387
Please cite this article as: Swami M al., Formulation and Evaluation of Mouth Dissolving Tablets of
Cinnarizine Hydrochloride and Domperidone Maleate. American Journal of PharmTech Research 2018.
Formulation and Evaluation of Mouth Dissolving Tablets of
Cinnarizine Hydrochloride and Domperidone Maleate
Mallinath M. Swami1* Mhetre Rani M2., Atul S. Sayare2, Shrisundar Nikhil S2.
1. JSPM’s Rajarshi Shahu College of Pharmacy and Research, Tathawade, Pune-33,
Maharashtra, India.
2. Gandhi Natha Rangji College of D. Pharmacy , Solapur
ABSTRACT
The purpose of this study is to prepare Mouth dissolving tablets of Cinnarizine HCl and
Domperidone Maleate by Direct compression method. In the present research study,
Crosspovidone (CP) and Sodium Starch Glycolate (SSG) was taken as super disintegrant. Here the
Cinnarizine HCl (H1 anti-histaminics) and Domperidone (anti-emetic) is taken as the model drug for
the study and direct compression as a method for preparation of the Mouth Dissolving Tablet. These
combination of drugs are ideal for the prevention of symptoms caused by vestibular disorders
and vertigo/motion sickness, nausea, dizziness, headache, vomiting, sensation of fullness when
there is a delay in gastric emptying. A 32 full factorial design was applied to investigate the
combine effect of two formulation variable CP(X1) and SSG(X2). Here the concentration of
both Superdisintegrants was taken as independent variable, X1 and X2 respectively. I.R. and
DSC study revealed that all polymers and excipients used were compatible with the drugs. All the
pre and post-compression evaluation parameters shows good results and all batches are within
acceptable limits. Mouths feel test gives pleasant sensation on human subjects when tablets are
put it on tongue. The effect of Disintegration time (Y1) and % Drug release (Y2) were investigated
as dependent parameters. From optimization data results that, among all the formulation F6 Batch
was best formulation. The optimized batch obtained from the factorial design was compared
with the marketed products. The stability study of the optimized batch is also done at 40ºC and
75%RH.
Keywords: 32 Full factorial design, Cinnarizine HCl, Domperidone Maleate, Crosspovidone,
Sodium starch glycolate, Disintegration time, and Percentage drug release.
*Corresponding Author Email: [email protected] Received 19 August 2018, Accepted 08 September 2018
Journal home page: http://www.ajptr.com/
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INTRODUCTION
Many patients especially children and elderly have difficulty in swallowing tablets and capsules
and consequently unable to take medicine as prescribed. Almost 50% of the population is
affected by such problem, resulting in the high incidence of non compliance and ineffective
therapy. Most pharmaceutical forms for oral administration are formulated for direct ingestion, or
for chewing, or for prior dispersion and/or dissolution in water; some of them are absorbed in the
mouth. To obviate the problems associated with conventional dosage forms, orally Mouth
dissolving tablets have been developed, which combine hardness, dosage uniformity, stability and
other parameters, with extremely easy administration, since no water is required for
swallowing the tablets and they are thus suitable for geriatric, pediatric and traveling patients.
MDTs can be prepared by different methods as direct compression, freezedrying, spray drying,
sublimation and wet granulation method. The aim of this study was to formulate MDTs with
sufficient mechanical integrity and to achieve faster disintegration in the oral cavity without
water. To achieve this goal, mannitol used as diluent and Lactose and sodium saccharin as
sweetening agent for the formulation of tablets. Attempts were made to enhance dissolution rate
along with faster disintegration using superdisintegrants like Cross-povidone and Sodium starch
glycolate (SSG) in the formulation of tablets. Two model drugs, with poor aqueous solubility
Cinnarizine HCl (H1 anti-histaminics) and Domperidone (anti-emetic) were selected for the
studies. These combination of drugs are ideal for the prevention of symptoms caused by
vestibular disorders and vertigo/motion sickness, nausea, dizziness, headache, vomiting, sensation
of fullness when there is a delay in gastric emptying.
MATERIALS AND METHOD
Materials
Cinnarizine hydrochloride (Emcure Pharmaceutical Ltd., Pune, India) and Domperidone maleate
(Centaur Pharmaceutical Ltd., Pune, India) was kindly supplied as gift samples. Cross-
povidone (CP) and Sodium starch glycolate (SSG) was obtained from our laboratory. anhydrous
lactose, Mannitol and magnesium stearate ( Oxford Chemicals, Pune, India) were purchased. All
other chemicals and solvents used were of analytical grade.
Methods
Both the drugs and superdisintegrants are mixed thoroughly along with formulation additives.
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12 station rotatory tablet compression machine was used to manufacture the Mouth dissolving
tablets in order to get sufficient mechanical strength. All the formulation batches were formulated
in accordance with the Optimization technique studies.
Compatibility study
Compatibility study with excipients was carried out by FTIR and DSC. The pure drug and
excipients were subjected to FTIR and DSC studies. Then the spectrum obtained after studies were
compared with standard spectrum of the drug (11).
Evaluation Parameters
pre-compression parameters
Characteristics of powder mixtures were determined by Angle of repose, Bulk density, Tapped
density, Compression index, Hausner’s ratio
Angle of repose:
A funnel was filled to the brim and the test sample was allowed to flow smoothly through the
orifice under gravity. From the cone formed on a graph sheet was taken to measure the area of
pile, thereby, evaluating the flowability of the powders. Height of the pile is then measured.
Angle of repose for powder mixture is calculated by formula: tan θ = h/r
θ = tan-1 (h/r)
Where, θ is the angle of repose
h is the height, r is the radius.
Bulk density and Tapped density:
The accurately weighed amount of sample taken in a 25ml measuring cylinder of mixture
powder measured/recorded the volume of packing and tapped 100 times on a plane hard wooden
surface and tapped volume of packing recorded and LBD and TBD calculated by following
formula:
LBD (Loose Bulk Density) = Weight of Powder / Volume of Packing
TBD (Tapped Bulk Density) = Weight of Powder / Tapped Volume of Packing
Percentage Compressibility:
Percent compressibility of powder mix was determined by Carr’s compressibility index calculated
by following formula.
Carr’s Index % = TBD - LBD/ TBD x 100
Hausner’s Ratio:
A similar index has been defined by Hausner’s, Hausner ratio as an indication of powder flow
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Hausner ratio = Tapped density/ Loose density
Experimental design for preparation of tablet
A central composite design was used for optimization procedure. It is suitable for investigating
the quadratic response surfaces and for constructing a second-order polynomial model, thus
enabling optimization of the tablet. Mathematical modeling and response surface modeling were
performed by employing Design-Expert® software Version 8.1. Combination containing drugs for
MDT were prepared based on central composite designs. Quantity of CP (X1) and SSG (X2) were
selected as two independent variables. Three levels determined from preliminary studies of each
variable were selected and nine possible batches were prepared using different levels of variables
given in table (18,19,20).
Table 1 Different batches with their respective compositions as per 32 factorial design
Batch code CP (X1) SSG (X2)
F1 +1 0
F2 -1 -1
F3 0 0
F4 -1 0
F5 0 +1
F6 -1 +1
F7 0 -1
F8 +1 -1
F9 +1 0
Table 2:32 full factorial design layout
Sr.
no.
Coded
value
Amount of Crosspovidone
(X1) in mg
Amount of sodium starch
glycolate(X2) in mg
1 -1 12 12
2 0 15 18 3 +1 18 24
Table 3 Composition profile for preparing mouth dissolving tablet by optimization
technique
Composition F1 F2 F3 F4 F5 F6 F7 F8 F9
CIN 20 20 20 20 20 20 20 20 20 DOM 15 15 15 15 15 15 15 15 15 CP 18 12 15 12 15 12 15 18 18
SSG 18 12 18 18 24 24 12 12 18 Mannitol 100 100 100 100 100 100 100 100 100
Lactose 69 75 67 85 61 64 73 75 64
Sodium Sacc. 10 10 10 10 10 10 10 10 10
Mg. Stearate 5 5 5 5 5 5 5 5 5
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Total(mg) 250 250 250 250 250 250 250 250 250
Post-compression parameters
Prepared mouth dissolving tablets was evaluated for evaluation parameters like thickness and
diameter, friability, weight variation, disintegration test, drug content uniformity.
Hardness and thickness:
Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The
hardness of the tablets were determined using Monsanto hardness tester. It is expressed in kg/cm2.
Three tablets were randomly picked and hardness of the same tablets from each formulation were
determined. The mean and standard deviation values were also calculated.
Friability study:
The friability of tablets were determined using Roche Friabilator. It is expressed in percentage
(%). Twenty tablets were initially weighed (W initial) and transferred into friabilator. The
friabilator was operated at 25 rpm for 4 minutes or run up to 100 revolutions.
Drug content:
Twenty tablets were weighed and average weight was calculated. The tablets were crushed into
fine powder. Tablet powder equivalent to 10mg of CIN and DOM was transferred to 100ml
volumetric flask and ultra sonicated for 10min. The volume was made up to the mark with pH6.8
phosphate buffer solution. The resulting solution was then filtered through a Whatmann filter
paper and were analyzed at 254.0nm and 284.0nm of CIN and DOM respectively.
Weight variation test:
Twenty tablets were selected randomly from each formulation and weighed individually to check
for weight variation. A little variation is allowed in the weight of a tablet by the US
Pharmacopoeia.
Wetting time:
The method was applied to measure tablet wetting time. A piece of tissue paper folded twice was
placed in a small petridish (i.d. = 6.5 cm) containing 6 ml of water, a tablet was put on the paper,
and the time for complete wetting was measured.
Water absorption ratio:
A tablet was put on the paper and time required for complete wetting was measured. The wetted
tablet was then weighed. Water absorption ratio, R, was determined using equation -
R = 10 x Wa - Wb/Wb
Where, Wb = weight of the tablet before water absorption
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Wa = weight of the tablet after water absorption
In vitro dispersion time:
In vitro dispersion time was measured by dropping a tablet in a measuring cylinder containing 6 ml
of pH 6.8 (simulated saliva fluid). Three tablets from each formulation were randomly selected
and in vitro dispersion time was performed.
In vitro disintegration time:
Place three tablet in each of the 6 tubes of the basket. Add a disc to each tube and run the
apparatus using pH 6.8 (simulated saliva fluid) maintained at 37±0C as the immersion liquid. The
assembly should be raised and lowered between 30 cycles per minute in the pH 6.8 maintained at
37.50±0.5C.
Mouth feel and In vivo Disintegration:
To know mouth feel of the tablets, the human volunteers held the disintegrated particles in the
mouth for 30 seconds and the taste sensation felt was recorded and simultaneously the time taken
for complete disintegration of the tablet on the tongue was noted.
In vitro Dissolution Studies:
In vitro release studies were carried out using tablet dissolution test apparatus USP XXIII.
Dissolution medium: 900 ml of pH6.8 Phosphate Buffer Solution Temperature 37°C ± 5 RPM : 50
Tablet taken: One tablet (As per known drug content) Volume withdrawn: 5 ml every 2.5 min.
Dilution factor: 1The drug content was determined by simultaneous equation method by UV
spectrophotometer at λmax 254.0nm and 284.0nm taking absorptivity values of standard CIN and
DOM as described for the drug content method.
Comparison with Marketed product:
Optimized formulation was compared with marketed product of CIN and DOM tablet
preparations. Marketed formulation of CIN and DOM are evaluated for hardness, friability,
uniformity of drug content % cumulative drug release study and thickness.
Stability Studies:
Stability of a drug has been defined as the ability of a particular formulation, in a specific
container, to remain within its physical, chemical, therapeutic and toxicological specifications.
In the present study, stability studies were carried out at 40 º C±2ºC / 75% RH for a specific time
period up to 30 days for selected formulation.
RESULTS AND DISCUSSION
Both the drugs and superdisintegrants are mixed thoroughly along with formulation additives.
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12 station rotatory tablet compression machine was used to manufacture the Mouth dissolving
tablets in order to get sufficient mechanical strength. All the formulation batches were formulated
in accordance with the Optimization technique studies.
Compatibility studies by
FT-IR Studies:
A comparison between FT-IR spectra of the pure drug and the combination of drug with the
polymers, it was observed that all the characteristic peaks of CIN and DOM were present in the
combination spectra as well; thus indicating the compatibility of the drug with the polymers used.
The individual FT-IR spectra of the pure form of CIN and DOM, combination of drug and polymers
were shown in the Figure 1. All the characteristic peaks of CIN and DOM were present in Spectra
thus indicating compatibility between drug and excipients.
DSC Studies:
The DSC curve of pure CIN and DOM exhibited an initially flat profile, followed by a single
sharp endothermic peak representing the melting of the substance in the range 118 ºC -120 ºC and
137 ºC -139 ºC (Tonset = 231.2, T peak = 233.33 and ǻ Hfusion = -313.51 J/g). There was no shift
in the endotherms in the drug-excipient mixtures indicating compatibility of the drug with all the
excipients. The comparative DSC thermograms of the drugs, CP and SSG and drug-excipient
mixtures are depicted in Figure 2
Figure 1. Infrared spectrum of A-CIN B-DOM drugs, C -CP, D-SSG, E-Physical Mixture.
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Figure 2. DSC spectrum of A-CIN, B-DOM, C -CP, D-SSG, E-Physical Mixture
Evaluation of pre-Compression Parameters by Angle of repose, bulk density, tapped density,
compression index, Hausner’s ratio
Results of pre compression parameters of powder mixtures of MDT are shown in table 4 which
demonstrates that all the batches have good compressibility. Flow properties of all the batches
such as angle of repose and Hausner’s ratio were found to be within limits. But batch F6 shows
good flow property as compared with other batches. Therefore, batch F6 was selected for further
study.
Table 4 Angle of repose, bulk density, tapped density, compression index, Hausner’s ratio
Code Angle of
repose
Bulk
density(g/cm3)
Tapped
density(g/cm3)
Compressi-
bility index (%)
Hausner’s
Ratio
F1 28.38±0.12 0. 47±0.01 0.53±0.019 12.78±0.88 1.65±0.025
F2 27.32±0.21 0.52±0.023 0.58±0.022 14.18±0.42 1.68±0.013 F3 28.29±0.18 0.59±0.032 0.68±0.032 13.02±0.32 1.59±0.018
F4 27.21±0.41 0.54±0.029 0.60±0.048 14.25±0.44 1.54±0.015
F5 28.32±0.21 0.57±0.023 0.59±0.022 13.18±0.42 1.71±0.013
F6 28.42±0.32 0.54±0.013 0.55±0.036 14.62±0.41 1.54±0.054 F7 27.42±0.21 0.53±0.023 0.57±0.022 14.18±0.85 1.68±0.025
F8 28.32±0.21 0.42±0.023 0.68±0.022 14.22±0.42 1.69±0.013 F9 27.96±0.82 0.57±0.289 0.55±0.28 14.91±0.78 1.96±0.045 All the values are in mean ±SD, n=3.
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Evaluation of post compression parameters by weight variation, thickness, hardness, friability,
drug content
Results of post compression parameters of MDT are shown in table 5 which demonstrates that
Weight variation, Thickness, Hardness, Friability, Drug content. All the tablets of the test
product compiled with the official requirement. The friability indicates that the tablets are
compact and hard. But from above all the results batch F6 shows good post compression
property. Therefore, batch F6 was selected for further study.
Table 5 Evaluation of prepared tablets by weight variation, thickness, hardness, friability,
drug content
Batch
code
Weight
variation
Thickness
(mm)
Hardness
(kg/cm2)
Friability
(mg)
Drug
content (%)
F1 249.6±0.42 3.15±0.15 4.16±0.58 0.6633 99.06±0.116
F2 250.8±0.12 3.18±0.46 3.67±0.78 0.6103 98.04±0.114 F3 250.7±0.78 3.13±0.45 3.50±0.42 0.6035 98.44±0.451
F4 250.4±0.56 3.55±0.78 3.54±0.54 0.5336 98.54±0.116 F5 250.6±0.78 2.77±0.56 3.50±0.15 0.8200 99.16±0.145
F6 249.2±0.45 2.67±0.59 3.16±0.65 0.5336 100.06±0.44
F7 249.0±0.74 2.70±0.78 2.50±0.58 0.7496 99.06±0.44
F8 250.2±0.45 2.78±0.98 2.99±0.87 0.7107 99.06±0.674
F9 249.6±0.04 2.65±0.83 2.78±0.73 0.7305 99.99±0.78 All the values are in mean ±SD, n=3.
Wetting time:
Table 6 Wetting time of MDT at various time interval
Sr. no. Batch code Wetting time in seconds
1 F1 49±1.95
2 F2 60±0.59
3 F3 75±2.04 4 F4 40±1.45
5 F5 35±0.95
6 F6 25±1.00 7 F7 28±2.45
8 F8 50±1.45 9 F9 41±0.39 All values are in mean ±SD, n=3.
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Figure 3. Photographs showing wetting time of an Optimized F6 batch at different time
intervals.
Wetting time was determined for all the formulations. Wetting time of all the formulation were
more than 25 seconds, due to its rapid water-absorbing nature, involving both capillary and
swelling mechanisms of SSG and CP.
Water absorption ratio studies :
Table 8 Water absorption ratio
Sr. no. Batch code Water absorption ratio(%)
1 F1 73.57±1.05
2 F2 78.45±0.79
3 F3 81.29±1.56
4 F4 86.78±2.56 5 F5 91.89±0.95
6 F6 95.45±1.00 7 F7 88.45±2.45
8 F8 90.56±2.48
9 F9 41.59±0.39
Results reveals that in Table 8. water absorption ratio also in acceptable limits. Formulation batch
F6 containing water absorption shows good absorptive characteristics to as that of other
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formulation studies. So, batch F6 was selected for further studies. All values are in mean ± SD,
n=3.
In-vitro Dispersion time studies:
Table 9 In-vitro Dispersion time
Sr. no. Batch code In- vitro Dispersion time in seconds
1 F1 37±2.30
2 F2 25±0.57
3 F3 30±2.04
4 F4 18±2.06
5 F5 35±0.56
6 F6 15±1.09
7 F7 29±2.45
8 F8 18±1.45
9 F9 25±0.39
All values are in mean ±SD, n=3.
The in vitro dispersion time also differs, direct compressed tablet shows decrease in in vitro
dispersion time as the concentration of CP and SSG increases. Table 9. shows, F6 shows fastest
dispersion time. Probably it may be due formation of dense capillary network structure in
directly compressed mouth dissolving tablets. So, batch F6 was selected for further studies.
In-vitro disintegration studies:
Table 10 In-vitro disintegration studies.
Sr.no. Batch code In-vitro Disintegration time in seconds
1 F1 58±1.25
2 F2 50±1.00
3 F3 48±1.22 4 F4 56±2.44
5 F5 44±1.24 6 F6 38±1.00
7 F7 40±2.26
8 F8 48±0.58
9 F9 60±0.50
All values are in mean ±SD, n=3.
When CP and SSG are combined with the water soluble mannitol, it shows the shorter
disintegration time than other diluents. This may be attributed to the high water solubility of
mannitol which may leaves pores in the tablet. This test reveals that by combination of these
superdisintegrants along with lactose powder it gives faster disintegration rate. Result of
remaining batches are listed in table 10. Photographs showing of an optimized F6 batch at
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different time intervals. Therefore, batch F6 shows fast disintegration time as compared to other
batches. So, batch F6 was selected for further studies.
Mouth feel and In-vivo Disintegration
Table 11 Mouth feel and In-vivo Disintegration
Code Mouth feel In-vivo Disintegration time(sec)
F1 + 42
F2 - 36 F3 + 32 F4 + 30
F5 + 28
F6 + 24
F7 + 39
F8 + 34 F9 - 40
All values are in mean ±SD, n=3.
‘+’ sign indicates Good mouth feel ‘-‘ sign indicates Poor mouth feel
The result of the mouth feel evaluation by taste panel has been summarized in table 11. All the
members of taste evaluation panel reported the formulation from good to poor mouth feel.
Except F2 and F9 all remaining batches shows good mouth feel when kept on tongue of subjects
for 30 seconds.
The time taken for complete disintegration of the tablet on the tongue was noted for In-vivo
disintegration time studies. study reveals that, batch F6 shows faster disintegration time than other
batches. After the test, mouth was washed with distilled water.
Figure 5. In vitro Dissolution Profile of the Formulations F1, F2, F3, F4
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In vitro Drug Dissolution studies:
Figure 6. In vitro Dissolution Profile of the Formulations F5, F6, F7, F8, F9
The results of in-vitro dissolution methods was performed in phosphate buffer of pH6.8 for
complete drug release having maintained temperature of 37±0.2ºC. All the batches of MDT
showed fast disintegration and drug release in phosphate buffer of pH6.8. Although, the drug
release in MDT of all batches was quiet rapid one, the composition of MDT shows significant
effect on initial drug release. batch F6 showed more than 99% drug release within 60 minutes. F6
was considered as the optimal Mouth dissolving tablet formulation among all of the nine
formulations tested in this study.
Experiments of 32 full factorial design:
To develop mouth-dissolving tablet, amount of CP and SSG are important parameters affecting the
DT and Disso. T. The optimization strategy was carried out with the aim of finding optimu m amount
of CP and SSG to achieve mouth-dissolving tablet.
Multiple regression and mathematical model building:
The targeted response parameters were statistically analyzed by applying one-way ANOVA
(analysis of variance), at 5% significance level and the significance of the model was estimated
using the statistical Design-Expert. The individual parameters were evaluated using F-test and
mathematical relationship was generated between the factors X (independent variables) and
responses Y (dependent variables) using multiple linear regression analysis, for determining the
levels of factors which yield optimum DT and Disso. T. [Table 12].
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Table 12. 32 Full factorial design of optimization techniques for MDT
CODE STD RUN CP (X1) SSG (X2) DT (Sec) DR (%)
F1 7 1 12 24 48 85
F2 2 2 15 12 34 81
F3 9 3 18 24 28 87 F4 3 4 18 12 59 92 F5 1 5 12 12 32 95 F6 5 6 15 18 23 99
F7 4 7 12 18 52 91 F8 6 8 18 18 25 96 F9 8 9 15 24 42 83
A polynomial equation was used to study the effect of variables on different evaluation responses
(Y), where the coefficients in the equation (β0, β1, β2 and β12) were related to the effects and
interactions of the factors. A second-order polynomial regression equation that fitted to the data is
as follows:
Y = β0 + β1X1 + β2X2 + β1X2 1 + β2X2 2 + β12X1X2
where, β0 is the arithmetic mean response of nine batches, β1 and β2 coefficients of factor X1 and
X2 and β12 the coefficient of interaction of X1 and X2. The interaction (X1, X2) shows how the
dependent variable changes when two or more factors are simultaneously changed. Design-Expert
was used to obtain values of coefficients in the equation and f-statistics were used to identify
statistically significant terms. In Table 13, factor effects of 32 full factorial design model and
associated P-values for the responses Y1 and Y2 are presented. A factor is considered to influence
the response if the P-value is less than 0.05. The final equations of the responses are given below:
Table 13 Estimation of regression coefficients for different response variables
Coefficient Response variables (Y)
β0 (Intercept) 51.04 0.9846 Β1 -11.96 0.2489 Β2 0.5 -0.1.925
Β12 0.000 0.149 B11 0.000 0.2426
Β22 0.000 0.0687
R2 0.9778 0.5708
F* 87.59 0.73 P 0.0071 0.6108
where, β0, arithmetic mean response of nine batches; β1 and β2 coefficients of factor X1 and X2;
β12, β11, β22, coefficient of interaction of X1 and X2. *Significant level is set at 5%. A bold value
has P-value less than 0.05, hence the corresponding factors are considered to significantly influence
the response.
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Disso (Y1) = 51.04 - 0.03* X1 + 0.025* X2 - 0.000030* X1*X2 +0.07*X22+ 0.001133*X10
D. T. (Y2) = 0.9846 + 2.50*X1 - 1.25*X2 - 3.75*X1*X2 -0.73*X1.5- 1.09*X22
The equations represent the quantitative effect of factors (X1 and X2) upon the responses (Y1 and
Y2). Coefficients with one factor represent the effect of that particular factor while the
coefficients with more than one factor and those with second-order terms represent the
interaction between those factors and the quadratic nature of the phenomena, respectively.
Positive sign in front of the terms indicates synergistic effect while negative sign indicates
antagonistic effect of the factors.
Response surface analysis:
The quadratic models generated by regression analysis were used to construct 3D response
surface plots in which response parameter Y was represented by a curvature surface as a function of
X.
A linear synergistic relationship between the two independent variables on response Y1 as was
also evident from the P-value listed in Table 17. and it depicts curvilinear relationship for
response Y2 with ‘a region of maxima’ lying between the lower to higher levels of the factors. A
numerical optimization technique using the desirability approach was employed to develop a new
formulation with the desired responses.
For Disintegration time-R1Conc.of SSG, X1 = 18 mg
For % Drug release-R2 Conc. of CP, X2 = 99.33%
Validation of response surface methodology:
In order to assess the reliability of the developed mathematical model and dissolution test of the
formulated pellets corresponding to the predicted optimum CP and SSG was performed. For each
of these test run, responses were estimated by use of the generated mathematical model and by the
experimental procedures. For the optimized batch predicted values for DT Y1 is 37.35 s while the
experimental values for responses Y1 is 36.53 s, respectively. The tablets prepared according to
optimum formulation achieved Disso. T Y2 1.081mm while the experimental values for response
Y2 is 1.080 mm. The release profile of optimized tablet formulation.
Design-Expert® Software
Factor Coding: Actual R1 DT
59
23
60
X1 = A: A Cross-povidone X2 = B: B SSG
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50
Actual Factor
C: C Mannitol = 120.00 40
30
20
24.00
21.00
18.00
B: B Sodium starch glycolate
15.00
18.00
17.00
16.00
15.00
14.00
13.00
12.00 12.00
A: A Cross-povidone
Figure 7. Surface response plot showing the influence of varying concentration of CP and
SSG levels of an optimized F6 batch for Disintegration time.
Swami et. al., Am. J. PharmTech Res. 2018;8(5) ISSN: 2249-3387
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Figure 8. Surface response plot showing the influence of varying concentration of CP and
SSG levels of an optimized F6 batch for % Drug release.
Design-Expert® Software
Factor Coding: Actual R2 %DR
99
81
X1 = A: A Cross-povidone
X2 = B: B SSG
Actual Factor C: C Mannitol = 120.00
100
98
96
94
92
90
24.00
21.00
18.00
15.00
B: B Sodium starch glycolat18.00
17.00
Singh et. al., Am. J. PharmTech Res. 2018; 8(5) ISSN: 2249-3387
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R 2
16.00
15.00
14.00
13.00 A: A Cross-povidone
12.00 12.00
The results of a 32 full factorial design revealed that the amount of CP and SSG significantly
affect the dependent variables, Disintegration time, and Drug release.
Figure 9. Comparison of optimized F6 batch with conventional marketed tablet
It is thus concluded that by adopting a systematic formulation approach, an optimum point can
be reached in the shortest time with minimum efforts. Direct compression method would be an
effective alternative approach compared with the use of more expensive adjuvants in the
formulation of MDT.
Comparison of optimized formulation with conventional marketed tablet
Table 13. Comparison of optimized formulation with conventional marketed tablet
Sr.no. Time
(min.)
Cumulative % drug release
from conventional marketed
tablet
Cumulative % drug release
from optimized F6 batch
STUGIL CIN+DOM CIN DOM
1 2.5 1.81±3.84 19.1 ±2.8 21.05±1.5 2 5 3.45±1.69 31.00±3.8 26.35±2.9
3 7.5 6.29±0.67 42.97±2.1 34.26±2.4
4 10 8.93±1.45 51.73±3.1 41.36±1.9
5 15 9.81±3.25 58.78±1.9 50.11±2.6 6 30 14.33±2.88 76.12±1.3 71.68±2.1 7 45 19.54±1.89 81.22±1.5 90.86±2.7
8 60 24.70±3.78 99.89±2.3 99.67±2.8
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In-vitro dissolution studies for batch F6 was carried out using tablet dissolution test apparatus USP
XXIII at 50rpm, which shows that the drug release was more than 90% within 45 min which is
better than conventional marketed tablet. The results are shown in Table 13 and a plot of
comparison is shown in figure 9.
Stability studies
Table 14. Stability studies of an optimized batch
Code Hardness
(kg/cm2)
Friability
(%)
Disintegration
(sec)
Wetting
time (sec)
Drug
content(%)
F6 3.16±0.65 0.5336 35 26 99.96±0.445
All the values are in mean ± SD, n=3.
Selected Formulations batch F6 Stored at 40ºC /75% RH Hardness (kg/cm2), Disintegration time
(sec), Wetting time(sec) Formulation Code Tested after time (in days) Mean ± SD (n=3) Drug
content uniformity(n=3) Friability %
The factorial design batches were subjected to short term stability studies at 40°C and 75% RH
for one months. Studies indicated that no significant change in appearance of the tablets,
Disintegration time, wetting time, Drug content was observed.
SUMMARY AND CONCLUSION
Summary
The aim of this research work was to develop the mouth dissolving tablets of Cinnarizine and
Domperidone. Mouth dissolving tablets were formulated to give quick onset of action by rapidly
disintegrating in a matter of seconds without the need of water and also to achieve better patient
compliance. After performing compatibility studies by IR spectrophotometry along with DSC
thermogram analysis and conforming no interaction of drugs with polymers. Mouth dissolving
tablets of cinnarizine and Domperidone were formulated by using
32 full factorial optimization technique
By Direct Compression method
Conclusion
The mouth dissolving tablets of cinnarizine and Domperidone can be formulated by direct
compression method and also by 32 full factorial optimization study. The FT-IR spectras and DSC
Thermogram revealed that, superdisintegrants and formulation additives used were compatible
with drugs. Hardness and friability of all the formulations indicated tablets were mechanically
stable and percentage weight variation and drug content uniformity found within limits.
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Sodium starch glycolate, cross-povidone and Mannitol in combination (in direct compression
technique) acts as super disintegrants, which is revealed by in vitro disintegration time, in vivo
disintegration time, in vitro dispersion time and wetting time results. Water absorption ratio
indicates well absorptivity in all formulations. In vitro release studies revealed that 99% of drug
release formulations F6 batch was within 60 mins. Best selected formulations F6 batch found to be
stable.
The results of optimization study showed that all two independent variables had significant effect
on the selected responses.
Overall, Optimization study reveals that as the concentration of Crosspovidone and sodium
starch glycolate increases, bioavailability increases, which is more beneficial for better patient
compliance. formulations F6 tablets disintegrated rapidly with good results. Direct compression
methods can be utilized in preparing mouth dissolving tablets.
ACKNOWLEDGEMENTS
The authors are thankful to Emcure Pharmaceutcal Ltd, Pune, India, and Centaur
Pharmaceutical Ltd, Pune, India, and Rajshi shahu college of pharmacy and research Pune, India,
for generously giving the samples of CIN and DOM and for providing facilities, respectively.
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